Trastuzumab deruxtecan

Trastuzumab deruxtecan (also known as DS-8201) is a monoclonal antibody drug conjugate used in the treatment of certain types of breast cancer. It is specifically designed for the treatment of patients with HER2-positive breast cancer that is unresectable or metastatic and who have received two or more prior anti-HER2-based regimens in the metastatic setting. Trastuzumab deruxtecan combines a HER2-targeted antibody, similar to trastuzumab, with a cytotoxic drug, allowing for the direct delivery of the chemotherapy to the cancer cells while minimizing exposure to the rest of the body.

Mechanism of Action

Trastuzumab deruxtecan works through a dual mechanism. Firstly, the trastuzumab component binds to the HER2 protein on the surface of cancer cells. HER2 is overexpressed in some breast cancer cells, promoting their growth. By binding to HER2, trastuzumab can inhibit the proliferation of these cancer cells. Secondly, once bound, the conjugate is internalized by the cancer cell, where the cytotoxic agent (deruxtecan) is released. Deruxtecan induces DNA damage, leading to cell death. This targeted approach allows for the delivery of high concentrations of chemotherapy to the cancer cells with reduced systemic toxicity.

Clinical Trials

Clinical trials have demonstrated the efficacy of trastuzumab deruxtecan in patients with HER2-positive metastatic breast cancer. The pivotal phase II trial, known as DESTINY-Breast01, showed a significant improvement in overall response rate and progression-free survival in patients treated with trastuzumab deruxtecan compared to standard therapies. Further studies are ongoing to evaluate its effectiveness in other HER2-expressing cancers, including gastric and non-small cell lung cancers.

Adverse Effects

The use of trastuzumab deruxtecan is associated with several potential adverse effects. The most common include nausea, fatigue, vomiting, alopecia, and constipation. More serious side effects can occur, including interstitial lung disease/pneumonitis, neutropenia, and left ventricular dysfunction. Patients receiving trastuzumab deruxtecan should be monitored for signs of these adverse effects, and treatment should be adjusted accordingly.

Approval

Trastuzumab deruxtecan received accelerated approval from the U.S. Food and Drug Administration (FDA) in December 2019 for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2-based regimens in the metastatic setting. This approval was based on the results of the DESTINY-Breast01 trial. Subsequent approvals in other jurisdictions have followed, reflecting its potential as a significant advancement in the treatment of HER2-positive breast cancer.

Conclusion

Trastuzumab deruxtecan represents a significant advancement in the treatment of HER2-positive breast cancer, offering hope to patients who have exhausted other treatment options. Its targeted mechanism of action allows for the delivery of potent chemotherapy directly to cancer cells, improving efficacy while reducing systemic side effects. Ongoing research and clinical trials will further elucidate its role in the treatment of other HER2-expressing cancers.

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